Adjuvant Drugs Research Articles

Effects of Resveratrol on Mouse B16 Melanoma Cell Proliferation through the SHCBP1-ERK1/2 Signaling Pathway.

Melanoma originates from the malignant mutational transformation of melanocytes in the basal layer of the epidermal layer of the skin. It can easily spread and metastasize in the early stage, resulting in a poor prognosis. Therefore, it is particularly important to find effective antitumor adjuvant drugs to inhibit the occurrence and development of melanoma. In this study, we found that resveratrol, a polyphenolic compound from grape plants, can significantly inhibit the proliferation, colony formation and migration of mouse melanoma B16 cells. Notably, resveratrol was also found to inhibit the expression of SHCBP1 in B16 cells. Transcriptional analysis and cellular studies showed that SHCBP1 can activate the MAPK/ERK signaling pathway to regulate cyclin expression and promote the G1/S phase transition of the cell cycle by upregulating ERK1/2 phosphorylation levels. Resveratrol further downregulates the phosphorylation level of ERK1/2 by inhibiting SHCBP1 expression, thus inhibiting tumor cell proliferation. In conclusion, resveratrol inhibits the proliferation of B16 cells by regulating the ERK1/2 signaling pathway through SHCBP1. As an upstream protein of the ERK1/2 signaling pathway, SHCBP1 may be involved in the process of resveratrol-mediated inhibition of tumor cell proliferation.

Bibliometric Analysis and Systemic Review of Cantharidin Research Worldwide.

Cantharidin (CTD), a natural toxic compound from blister beetle Mylabris, has been used for cancer treatment for millenary. CTD and its analogs have become mainstream adjuvant drugs with radiotherapy and chemotherapy in clinical applications. However, the detailed pharmacology mechanism of CTD was not fully elucidated. Publications of CTD were collected from the Web of Science Core Collection database from 1991 to 2023 using CiteSpace, VOSviewer, and Scimago Graphica software. A total of 1,611 publications of CTD were mainly published in China and the United States. The University of Newcastle has published the most researches. Mcclusey, Adam, Sakoff, Jennette, and Zhang, Yalin had the most CTD publications with higher H. Notably, CTD researches were mainly published in Bioorganic & Medicinal Chemistry Letters and the Journal of Biological Chemistry. Cluster profile results revealed that protein phosphatase 2A (PP2A), human gallbladder carcinoma, Aidi injection, and cell apoptosis were the hotspots. Concentration on the pharmacology function of PP2A subunit regulation, hepatotoxicity, nephrotoxicity, and cardiotoxicity mechanism should be strengthened in the future. Bibliometric analysis combined with a systemic review of CTD research first revealed that PP2A and CTD analogs were the knowledge base of CTD, and PP2A subunit regulation and toxic mechanism could be the frontiers of CTD.

Effect of Calcitriol in Inhibiting the Cancer Cell Growth and Promoting Apoptosis in ErbB2-positive Breast Cancer Cells.

Targeted therapies, specifically ErbB family tyrosine kinase inhibitors, have demonstrated potential for improving outcomes in patients with ErbB2-positive breast cancer. Despite their effectiveness, these therapies are associated with limitations, including high costs, side effects, drug resistance, lack of specificity, and toxicity. To overcome these challenges, drug repurposing has emerged as a promising strategy in breast cancer treatment. The aim of this investigation was to assess the influence of calcitriol on breast cancer cell lines expressing ErbB2 and comparing its effects with the conventional treatment, neratinib. We employed an MTT test to determine cell viability and utilized staining techniques to assess cell apoptosis. Flow cytometry was used to evaluate cell cycle arrest, while a scratch wound healing test was performed to examine cancer cell migration ability. Additionally, gene expression studies were conducted for calcitriol and neratinib to support our hypothesis regarding the ErbB2 gene. The repurposing of calcitriol demonstrated enhanced efficacy in suppressing cancer cell growth in ErbB2- positive breast cancer. Proportionally, calcitriol significantly reduced the viability of SK-BR-3 cells, similar to neratinib. Furthermore, calcitriol exhibited significant cytotoxicity against neratinib and substantially reduced breast cancer cell growth. These findings were corroborated by the wound healing assay, cell cycle arrest analysis, and gene expression studies, demonstrating comparable efficacy to the standard treatment, neratinib. The findings from this investigation offer compelling proof that highlights the promising role of calcitriol as an adjuvant drug with antiproliferative and antitumoral effects in the management of ErbB2-positive breast carcinoma patients. Therefore, we recommend further evaluation of calcitriol in clinical settings, particularly for the treatment of ErbB2-positive breast cancer, as it shows promise as a valuable therapeutic option.

Anaesthesia in Veterinary Oncology: The Effects of Surgery, Volatile and Intravenous Anaesthetics on the Immune System and Tumour Spread.

Throughout the course of oncological disease, the majority of patients require surgical, anaesthetic and analgesic intervention. However, during the perioperative period, anaesthetic agents and techniques, surgical tissue trauma, adjuvant drugs for local pain and inflammation and other non-pharmacological factors, such as blood transfusions, hydration, temperature and nutrition, may influence the prognosis of the disease. These factors significantly impact the oncologic patient's immune response, which is the primary barrier to tumour progress, promoting a window of vulnerability for its dissemination and recurrence. More research is required to ascertain which anaesthetics and techniques have immunoprotective and anti-tumour effects, which will contribute to developing novel anaesthetic strategies in veterinary medicine.

The inhibitory effect of berberine chloride hydrate on Streptococcus mutans biofilm formation at different pH values.

Streptococcus mutans (S. mutans) is one of the major cariogenic bacteria of dental caries owing to its ability to adhere to tooth surfaces and biofilm formation. Berberine chloride hydrate (BH), a quaternary ammonium salt alkaloid, has diverse pharmacological efforts against microorganisms. However, the effect of BH on S. mutans biofilm has not been reported. Considering that berberine is a quaternary ammonium salt alkaloid, which needs to adapt to a large variation in pH values and the acid resistance of S. mutans, we employed three groups including pH 5 (acidic), pH 8 (alkaline), and unprocessed group (neutral) to examine the antibiofilm activities of BH against S. mutans during different pH values. In this study, we found BH effectively suppresses S. mutans biofilm formation as well as its cariogenic virulence including acid production and EPS synthesis significantly, and the inhibitory effort was reduced under acidic condition whereas elevated under alkaline condition. In addition, we preliminarily explored the influence of pH values on the structural stability and biosafety of BHas well as the underlying mechanism of inhibition of S. mutans biofilm formation with BH. Our study showed BH could maintain a good structural stability and low toxicity to erythrocytes at different pH values. And BH could downregulate the expression of srtA, spaP, and gbpC, which play critical roles in the adhesion process, promoting bacterial colonization and biofilm formation. Furthermore, comX and ldh expression levels were downregulated in BH-treated group, which might explain its inhibitory effect on acid production.IMPORTANCEDental caries is a common chronic detrimental disease, which could cause a series of oral problem including oral pain, difficulties in eating, and so on. Recently, many natural products have been considered as fundamental sources of therapeutic drugs to prevent caries. Berberine as a plant extract showed good antibiofilm abilities against microorganism. Our study focuses on its antibiofilm abilities against S. mutans, which was defined as major cariogenic bacterium and explored the role of pH values and possible underlying mechanisms in the inhibitory effect of BH on S. mutans biofilm formation. This study demonstrated a promising prospect for BH as an adjuvant drug in the prevention and management of dental caries.

Spinal anesthesia for L5-S1 interlaminar endoscopic lumbar discectomy: a retrospective study

ObjectiveThis study aimed to report our experience with spinal anesthesia (SA) in patients undergoing L5-S1 interlaminar endoscopic lumbar discectomy (IELD) and clarify its advantages and disadvantages.MethodsOne hundred twelve patients who underwent IELD for an L5-S1 disc herniation under SA were retrospectively analyzed. SA with 0.5% ropivacaine was administered using a 27-gauge fine needle. Intraoperatively, the volume and level of SA, surgical time, blood loss, and cardiopulmonary complications were documented. Postoperative data was collected included the number of patients who ambulated on the day of surgery, incidence of complications and were then statistically analyzed.ResultsAnalgesia was complete throughout the entire operation in all patients and no other adjuvant intraoperative analgesic drugs were needed. Mean visual analog scale scores for intraoperative and early postoperative (24 h) pain were 0 and 2.43 ± 1.66. SA was administered at the L3-4 interspace in 34 patients (30.4%) and the L2-3 interspace in 78 (69.6%). Administration was successful with the first attempt in all patients. Mean operation time was 70.12 ± 6.52 min. Mean intraoperative blood loss volume was 20.71 ± 5.26 ml. Ninety-eight patients ambulated on the same day as surgery. Mean length of hospital stay was 24.36 ± 3.64 h. Dural injury without damaging the nerve root occurred in one patient. One patient experienced recurrent disc herniation. Intraoperative hypotension and respiratory distress occurred in five (4.5%) and three (2.7%) patients, respectively. Three patients (2.7%) received postoperative analgesia therapy and two (1.8%) experienced nausea. Two patients (1.8%) developed urinary retention. Spinal headache, cauda equina syndrome, and neurotoxicity did not occur.ConclusionSA can achieve satisfactory pain control for patients undergoing IELD with a low incidence of adverse events. SA may be a useful alternative to local and general anesthesia for IELD surgery. Future randomized controlled trials are warranted to investigate.

Effect of Cannabidiol on Human Peripheral Blood Mononuclear Cells and CD4+ T Cells.

Cannabidiol (CBD), the main non-psychoactive component of Cannabis sativa L., is widely used in therapy for the treatment of different diseases and as an adjuvant drug. Our aim was to assess the effects of CBD on proinflammatory cytokine production and cell proliferation in human peripheral blood mononuclear cells (PBMCs) and on CD4+ T lymphocyte differentiation, and, furthermore, to test CBD's ability to affect the functional properties of regulatory T cells (Treg). Experiments were performed on isolated PBMCs and purified CD4+ T lymphocytes obtained from the buffy coats of healthy subjects. Cytokines produced by CD4+ T cells were evaluated by flow cytometry and intracellular cytokine staining techniques. PBMC cytokine production was measured by an ELISA assay. Real-time PCR was used to assess the mRNA expression of cytokines and the key transcription factors (TFs) of CD4+ T cells. Finally, the proliferation of PBMC and CD4+ T effector cells (Teff), alone and in the presence of Treg, was assessed by flow cytometry. Results showed that CBD affects both the frequency of IL-4-producing CD4+ and of IFN-γ/IL-17-producing cells and dramatically decreases the mRNA levels of all TFs. Stimuli-induced cytokine mRNA expression was decreased while protein production was unaffected. CBD was unable to affect the ability of Treg to prevent Teff cell proliferation while it slightly increased PBMC proliferation. In conclusion, CBD may inhibit the expression of proinflammatory cytokines; however, the effect of CBD on cell proliferation suggests that this cannabinoid exerts a complex activity on human PBMCs and CD4+ T cells which deserves further investigation.

Research Progress of Vitamin K2 Related Signal Pathways: A Literature Review

Abstract: Vitamin K2 products were first applied to Japanese children, which can promote the growth of children's bones and eliminate their growing pain. At the same time, it does little harm to the human body, so it has attracted the attention of some scholars. Later, it was also proved to be effective in treating osteoporosis, especially for postmenopausal women. After years of research, some capabilities of VK2 have been discovered; it has been proved that it has great clinical value in treating osteoporosis, reducing intimal lipid deposition, diabetes, tumor, immune diseases, nervous system diseases and other diseases. There is no doubt that VK2 is an essential nutrient for human health, once vitamin K2 is deficient, it will cause a series of diseases. In recent years, some new evidences show that VK2 can also be used in leukemia and other diseases, which shows that VK2 still has great development potential. As a new adjuvant drug, VK2 has attracted worldwide attention and has been used in the clinic for many years. In this article, we mainly summarized the related research of VK2 in recent years, and expounded on several VK2-related signal pathways and the related mechanisms of these signal pathways in treating various diseases.

Repurposing of statins for Buruli Ulcer treatment: antimicrobial activity against Mycobacterium ulcerans.

Mycobacterium ulcerans causes Buruli Ulcer, a neglected infectious skin disease that typically progresses from an early non-ulcerative lesion to an ulcer with undermined edges. If not promptly treated, these lesions can lead to severe disfigurement and disability. The standard antibiotic regimen for Buruli Ulcer treatment has been oral rifampicin combined with intramuscular streptomycin administered daily for 8 weeks. However, there has been a recent shift toward replacing streptomycin with oral clarithromycin. Despite the advantages of this antibiotic regimen, it is limited by low compliance, associated side effects, and refractory efficacy for severe ulcerative lesions. Therefore, new drug candidates with a safer pharmacological spectrum and easier mode of administration are needed. Statins are lipid-lowering drugs broadly used for dyslipidemia treatment but have also been reported to have several pleiotropic effects, including antimicrobial activity against fungi, parasites, and bacteria. In the present study, we tested the susceptibility of M. ulcerans to several statins, namely atorvastatin, simvastatin, lovastatin and fluvastatin. Using broth microdilution assays and cultures of M. ulcerans-infected macrophages, we found that atorvastatin, simvastatin and fluvastatin had antimicrobial activity against M. ulcerans. Furthermore, when using the in vitro checkerboard assay, the combinatory additive effect of atorvastatin and fluvastatin with the standard antibiotics used for Buruli Ulcer treatment highlighted the potential of statins as adjuvant drugs. In conclusion, statins hold promise as potential treatment options for Buruli Ulcer. Further studies are necessary to validate their effectiveness and understand the mechanism of action of statins against M. ulcerans.

Clinical Trials of Carbon Ion Radiotherapy for Early-Stage Breast Cancer

Our institute conducted a clinical trial of curative partial breast irradiation using carbon ion radiotherapy (CIRT) to patients with stage 0 and I breast cancer since 2013. The purpose of this report is to evaluate treatment outcomes up to now. To date, we have conducted three clinical trials and one advanced medical treatment (NIRS 9404 Comprehensive Research). The first study (UMIN000010848: commonly known as Breast I trial) was 4-split irradiation for stage I low-risk patients aged 60 years or older, and the next clinical study (UMIN000029478: commonly known as Breast II trial) was for Tis-1N0M0 cases of 2 cm or less. On the other hand, 4-split irradiation using standard adjuvant drug therapy according to risk combined with whole breast irradiation by X-ray, the latest clinical trial (UMIN000046859: commonly known as Breast III trial) is a single irradiation for Tis-1N0M0 patients aged 50 years or older. be. In each phase I, the dose increase test was performed, and in phase II, treatment was performed with the recommended dose determined in phase I. Advanced medical care was provided in parallel with breast I for stage I breast cancer that was difficult or rejected to participate in breast I trial. By January 2023, 60 cases were enrolled. A total of 19 were enrolled In Breast I, 7 in Phase I, 12 in Phase II of the recommended dose of 60.0 Gy (RBE). A total of 14 were enrolled in the 9404 Comprehensive Research. A total of 17 were enrolled In Breast II, 5 cases in Phase I, 12 cases in Phase II of recommended dose 60.0 Gy (RBE). A total of 10 were enrolled in Breast III, 6 cases in Phase I, and 4 in Phase II of recommended dose 50.0 Gy (RBE). As acute adverse events, grade 2 of acute radiation dermatitis were observed in 1 case, grade 1 of acute radiation dermatitis was observed in 31 cases, and grade 1 of mastitis was observed in 6 cases. As a late adverse event, grade 3 of pneumonia of unknown causality were observed in one case, but there were no other problematic adverse events, and breast cosmetic outcome was excellent in all cases. Tumor disappearance after CIRT took 3 to 24 months. Local recurrence and axillary lymph node metastasis were observed in one high-risk case of advanced medical treatment who refused any other therapy. Two cases had ipsilateral intramammary metachronous breast cancer with different subtypes. To date, no other recurrences or metastases have been observed. CIRT for early-stage breast cancer is expected to be effective with mild adverse events, and it is considered meaningful to continue research.

Celecoxib attenuates neuroinflammation, reactive astrogliosis and promotes neuroprotection in young rats with experimental hydrocephalus

Hydrocephalus is a neurological condition with altered cerebrospinal fluid flow (CSF). The treatment is surgical and the most commonly used procedure is ventricle-peritoneal shunt. However, not all patients can undergo immediate surgery or achieve complete lesion reversal. Neuroprotective measures are valuable in such cases. It was evaluated whether the use of celecoxib, a selective inhibitor of COX-2, associated or not with ventricular-subcutaneous derivation, could offer benefits to the brain structures affected by experimental hydrocephalus. Seven-day-old male Wistar Hannover rats induced by intracisternal injection of kaolin 15% were used, divided into five groups with ten animals each: intact control (C), untreated hydrocephalus (H), hydrocephalus treated with celecoxib 20 mg/kg intraperitoneal (HTC), hydrocephalus treated with shunt (HTS) and hydrocephalus treated with shunt and celecoxib 20 mg/kg intraperitoneal (HTCS). Celecoxib was administered for 21 consecutive days, starting the day after hydrocephalus induction and continuing until the end of the experimental period. The surgery was performed seven days after inducing hydrocephalus. Multiple assessment methods were used, such as behavioral tests (water maze and open field), histological analysis (hematoxylin and eosin), immunohistochemistry (caspase-3, COX-2, and GFAP), and ELISA analysis of GFAP. The results of the behavioral and memory tests indicated that celecoxib improves the neurobehavioral response. The improvement can be attributed to the reduced neuroinflammation (p < 0.05), and astrogliosis (p < 0.05) in different brain regions. In conclusion, the results suggest that celecoxib holds great potential as an adjuvant neuroprotective drug for the treatment of experimental hydrocephalus.

The relationship between anesthesia and melatonin: a review.

Introduction: This comprehensive review delves into the intricate and multifaceted relationship between anesthesia and melatonin, aiming to provide essential insights for perioperative clinical anesthesiologists and stimulate interest in related research. Anesthesia and surgery have the potential to disrupt melatonin secretion, leading to sleep disorders, postoperative neurocognitive dysfunction and other symptoms. In comparison to previous reviews, this review provides a comprehensive summary of the various aspects linking melatonin and anesthesia, going beyond isolated perspectives. It explores the potential benefits of administering melatonin during the perioperative period, including alleviating anxiety, reducing pain, enhancing perioperative sleep quality, as well as demonstrating immunomodulatory and anti-tumor effects, potentially offering significant advantages for cancer surgery patients. Recent Findings: Anesthesia and surgery have a significant impact on melatonin secretion, the hormone crucial for maintaining circadian rhythms. These procedures disrupt the normal secretion of melatonin, leading to various adverse effects such as sleep disturbances, pain, and postoperative neurocognitive dysfunction. However, the administration of exogenous melatonin during the perioperative period has yielded promising results. It has been observed that perioperative melatonin supplementation can effectively reduce anxiety levels, improve pain management, enhance the quality of perioperative sleep, and potentially decrease the occurrence of postoperative delirium. In recent years, studies have found that melatonin has the potential to improve immune function and exhibit anti-cancer effects, further underscoring its potential advantages for patients undergoing cancer surgery. Summary: In summary, melatonin can serve as an adjuvant drug for anesthesia during the perioperative period. Its administration has demonstrated numerous positive effects, including anti-anxiety properties, sedation, analgesia, improved postoperative sleep, and the potential to reduce the incidence of postoperative delirium. Furthermore, its immune-modulating and anti-tumor effects make it particularly valuable for cancer surgery patients. However, further studies are required to determine the optimal dosage, long-term safety, and potential adverse reactions associated with melatonin administration.

Phenylethanoid glycosides derived from Cistanche deserticola promote neurological functions and the proliferation of neural stem cells for improving ischemic stroke

Phenylethanoid glycosides derived from Cistanche deserticola (PhGs) are plant-derived natural medicinal compounds that occur in many medicinal plants. This study aims to investigate whether PhGs treatment improves the stroke and its potential mechanisms. Adult male C57BL/6 J mice were administrated PhGs once daily for 7 days after MCAO surgery. The neurological score, and catwalk were evaluated on Day 1, 3 and 7 after ischemic stroke. Furthermore, triphenyl-2,3,5-tetrazoliumchloride (TTC) and hematoxylin-eosin (H&E) staining were used for evaluating the infarct volume and neuronal restoration. The effects of PhGs on NSCs proliferation were investigated in vitro and in vivo. Western blot was used to detect the proteins of Wnt/β-catenin signaling pathway. This study found that PhGs effectively improved the neurological functions in ischemic stroke mice. TTC and H&E staining demonstrated that PhGs not only reduced infarct volume, but also improved neuronal restoration. The immunohistochemistry and 5-Ethynyl-2-deoxyuridine (EdU) incorporation assays revealed that PhGs promoted the proliferation of neural stem cells (NSCs) in subventricular zone (SVZ). In addition, transcriptome analysis of NSCs showed that the Wnt/β-catenin signaling pathway was involved in the PhGs induced NSCs proliferation. Importantly, the related proteins in the Wnt/β-catenin signaling pathway were changed after PhGs treatment, including β-catenin, Wnt3a, GSK-3β, c-Myc. PhGs treatment improved the stroke through enhancing endogenous NSCs proliferation via activating Wnt/β-catenin signaling pathway. Due to its effect on the proliferation of NSCs, PhGs are a potential adjuvant therapeutic drug for post-stroke treatment.

Multimodal Analgesia in Pediatric Cancer Pain Management: A Retrospective Single-Center Study.

Objectives A multimodal approach to pain management, including potential interventional techniques, is suggested to achieve adequate pain control. This study discusses the techniques and medications employed to manage pain in pediatric oncology patients. Methodology This study included 90 patients under 18 years of age who underwent pain management in the algology clinic between 2002 and 2020. From the algology follow-up records, the following data were recorded: demographic information, follow-up time, cancer diagnosis and stage, cause and location of pain, systems involved, duration and intensity of pain, analgesic and adjuvant drugs prescribed, routes and duration of drug administration, complications, interventional procedures if performed, "pain intensity" scores prior to and following treatment, and daily and total analgesic consumption of the patients. Results The mean age was 11.4±4.1 years (min-max: 2-17). Leukemia and lymphoma were the most frequently diagnosed (30%). Of the 31 features identified in the staging, 27 (87.1%) were stage 4 at admission. The causes of pain in children were neoplasms in 81.2% (n = 73). At admission, 72.3% (n = 65) had severe pain for at least a month. It was determined that 90% (n = 81) of the patients were using opioids and 28.9% (n = 26) were using dual opioids. The mean tramadol dose was 129.0±97.9 mg/day (12-380 mg/day), and the mean morphine dose was 14.8±11.3 mg/day (1-52 mg/day). The mean transdermal fentanyl dose was 33.2±21.6 µgr/h (12-75 µgr/h). Adjuvant therapy was administered in 25.6% (n = 24) of the patients. Epidural catheterization was performed on 6.6% (n = 6) of the patients. The mean initial pain scores were 5.2±1.7, which decreased to 1.5±0.7 with a significant difference (p < 0.001). In the study, 93% (n = 84) of the patients had no pain management complications noted. Conclusions The pain level that pediatric cancer patients endure critically influences their and their family's quality of life. The fact that opioid-related adverse effects associated with pediatric pain management occur far less frequently than previously thought may help prevent opiophobia. Effective and safe analgesia can be provided with multimodal analgesia to manage pediatric cancer pain.

Non-chemotherapy adjuvant agents in TP53 mutant Ewing sarcoma

Ewing sarcoma (EWS) is a malignant tumor arising in bone or soft tissue that occurs in adolescent and young adult patients as well as adults later in life. Although non-metastatic EWS is typically responsive to treatment when newly diagnosed, relapsed cases have an unmet need for which no standard treatment approach exists. Recent phase III clinical trials for EWS comparing 7 vs 5 chemotherapy drugs have failed to improve survival. To extend the durability of remission for EWS, we investigated 3 non-chemotherapy adjuvant therapy drug candidates to be combined with chemotherapy. The efficacy of these adjuvant drugs was investigated via anchorage-dependent growth assays, anchorage-independent soft-agar colony formation assays and EWS xenograft mouse models. Enoxacin and entinostat were the most effective adjuvant drug in both long-term in vitro and in vivo adjuvant studies. In the context that enoxacin is an FDA-approved antibiotic, and that entinostat is an investigational agent not yet FDA-approved, we propose enoxacin as an adjuvant drug for further preclinical and clinical investigation in EWS patients.

The effect of protocatechuic acid on neuropathic pain and possible mechanism.

The goal of the research is to investigate the protocatechuic acid (PCA) potential action, a phenolic acid derivative, on pain induced by neuropathy and to determine its efficacy on activation of KATP type channels and A1 receptors. Neuropathic pain by cause of sciatic nerve damage was induced in Sprague-Dawley rats. Anti-allodynic and anti-hyperalgesic effects were evaluated with von Frey apparatus and Hargreave's plantar test apparatus, respectively. The effects of PCA at the doses of 75, 150 and 300 mg/kg, carbamazepine at the doses of 50 and 100 mg/kg, combination of low effective doses of PCA and carbamazepine were tested. Pretreatments 3 μg/kg DPCPX as adenosine A1 receptor antagonist and 60.7 nmol glibenclamide as KATP channel blocker were applied for mechanistic studies. PCA showed anti-allodynic and anti-hyperalgesic effects without impairing locomotor activity. In addition, the combination treatment was found to be more effective than the separate individual treatments of drugs. KATP channel activation related with A1 receptor stimulation makes a significant contribution to the anti-allodynia and anti-hyperalgesia induced by PCA. It can be said that PCA has similar effects with carbamazepine, which is used in clinical practice, and that PCA can take place as an adjuvant drug in neuropathic pain with the combination group. In addition, it is seen that the undesirable effects that drugs can cause alone can be avoided and a more effective treatment potential can be created with multiple mechanisms.

Differential Pharmacokinetic Interplay of Atorvastatin on Lacosamide and Levetiracetam on Experimental Convulsions in Mice.

The beneficial effects of statins, other than their hypocholesterolemia role, have been well documented, however, their use as an adjuvant drug with other antiseizure drugs, in the treatment of epilepsy is poorly understood. This study aimed to investigate the symbiotic effect of ATOR along with either lacosamide (LACO) or levetiracetam (LEVE) on experimentally induced epilepsy (Maximal electro-shock-MES or pentylenetetrazol- PTZ) in mice models. Conventional elevated-maze (EPM) and rotarod methods were performed to observe the behavioral effects. In both the animal models, we found that co-administration of ATOR along with LACO showed a significant reduction in hind-limb extension (HLE) and clonic convulsion (CC) responses, respectively, but not in the ATOR+LEVE treated group. Intriguingly, comparable Straub tail response and myoclonic convulsion as the diazepam (DIA) group were observed only in the ATOR+LACO treated group. Moreover, a significant muscle-grip strength was observed in both groups. Also, pharmacokinetic analysis has indicated that the mean plasma concentration of ATOR peaked at 2ndhr in the presence of LACO but marginally peaked in the presence of LEVE. An Insilico study has revealed that ATOR has a higher binding affinity toward neuronal sodium channels. This study has demonstrated that the plasma concentration of ATOR was potentiated in the presence of LACO, but not in the presence of LEVE and it has provided significant protection against both the electro and chemo-convulsive models in mice. This could be due to the symbiotic pharmacokinetic interplay of ATOR with LACO, and possibly, this interplay may interfere with sodium channel conductance.

Effects of intra-operative administration of intravenous dexmedetomidine on incidence of emergence phenomenon after general anaesthesia in adults; An observational study

Background: The occurrence of emergence agitation (EA) is the most common and practical problem faced in the immediate post-operative period during the process of Extubation under General Anaesthesia. Dexmedetomidine, an α2 adrenoceptor agonist is an excellent drug that has been shown effective to decrease the preoperative anxiety and smooth induction and emergence. Aims and Objectives: To assess the effect of intravenous dexmedetomidine primarily on EA and other complications that may occur during emergence from general anesthesia. Materials and Methods: 80 patients of either gender aged 18–65 years with ASA status I and II, undergoing various elective general and urological surgeries under general anesthesia were included in the study. Patients receiving adjuvant drug dexmedetomidine, were labelled as Group D (n=40) and those who didn’t receive any adjuvant were labelled as group C (n=40). Dexmedetomidine was given at 1 μg/kg and then maintained at infusion of 0.4 μg/kg/h till the end of the surgery for group D. The hemodynamic parameters and SpO2 were measured during the intraoperative period at various intervals of time till the end of surgery and also on arrival to the recovery room till patient was discharged from post-anesthesia care unit in both the groups. Results: The use of IV dexmedetomidine has proved significantly effective in prevention of incidence of EA with the overall incidence of agitation of 7.5% in Group D as compared to 42.5% in group C. Conclusion: Intraoperative administration of intravenous dexmedetomidine decreased the incidence of EA and other emergence phenomena like cough, pain and PONV with stable hemodynamics, safety profile, good analgesic properties and opioids sparing side effects.

Discovery of a Novel Ubenimex Derivative as a First-in-Class Dual CD13/Proteasome Inhibitor for the Treatment of Cancer.

The CD13 inhibitor ubenimex is used as an adjuvant drug with chemotherapy for the treatment of cancer due to its function as an immunoenhancer, but it has limitations in its cytotoxic efficacy. The proteasome inhibitor ixazomib is a landmark drug in the treatment of multiple myeloma with a high anti-cancer activity. Herein, we conjugated the pharmacophore of ubenimex and the boric acid of ixazomib to obtain a dual CD13 and proteasome inhibitor 7 (BC-05). BC-05 exhibited potent inhibitory activity on both human CD13 (IC50 = 0.13 μM) and the 20S proteasome (IC50 = 1.39 μM). Although BC-05 displayed lower anti-proliferative activity than that of ixazomib in vitro, an advantage was established in the in vivo anti-cancer efficacy and prolongation of survival time, which may be due to its anti-metastatic and immune-stimulating activity. A pharmacokinetic study revealed that BC-05 is a potentially orally active agent with an F% value of 24.9%. Moreover, BC-05 showed more favorable safety profiles than those of ixazomib in preliminary toxicity studies. Overall, the results indicate that BC-05 is a promising drug candidate for the treatment of multiple myeloma.

Design, synthesis, and biological evaluation of novel HDAC/CD13 dual inhibitors for the treatment of cancer

Aminopeptidase N (APN/CD13) plays a role in tumors progression, but its inhibitor lacks cytotoxicity and is used as an adjuvant drug in cancer treatment. Histone deacetylases (HDACs) are a type of epigenetic targets, and HDAC inhibitors are cytotoxic and exhibit synergistic effects with other anticancer agents. Herein, a novel series of HDAC/CD13 dual inhibitors were rationally designed and synthesized to combine the anti-metastasis and anti-invasion of CD13 inhibitor with the cytotoxic of HDAC inhibitor. The representative compound 12 exhibited more potent inhibitory activity against human CD13, HDAC1-3, and antiproliferative activity than positive controls bestatin and SAHA. Compound 12 effectively induced apoptosis in MV4-11 cells, while arresting A549 cells in G2/M phase. Moreover, 12 exhibited significantly better anti-metastasis and anti-invasion effects than mono-inhibitors 32 and 38, indicating that it is a promising anti-cancer agent for further investigation.